Summary of Work: We have continued to examine potential mechanisms by which D2 dopamine (DA) receptor- containing neurons may die during aging. A scenario is emerging which suggests that these cells are killed by dopamine oxidation and toxicity leading to apoptosis. The signal transduction events which mediate this process have been studied, in vitro, in a 293 cell model as well as in neurons cultured from neonatal rat striata. DA activates the JNK pathway in both cell types, including increases in JNK activity, phosphorylation of c-Jun, and subsequent increase in c-Jun protein. Transient expression of a dominant negative mutant, SEK1, an upstream kinase of JNK prevents both dopamine induced JNK activation and apoptosis. A dominant negative c-Jun mutant, FLAG 169 also reduces dopamine induced apoptotic death. Similar phenomena occur in vivo following direct intrastriatal injection, and in light of the long term exposure of these neurons to dopamine over the lifespan, provide supporting evidence for this mechanism of neuronal death.